Benzoheterocyclicalkyl derivatives of 4-(2-keto -1-benzimidazolinyl)-piperidine 4-(2-keto - 1 - benzimidazolinyl) -1 2 3 6 tetrahydropyridine 1 - phenyl - 1 3 8-triazaspiro(4 5)decan - 4 - one and 2 4 9-triazaspiro(5 5)undecan-1 3 5-trione

ABSTRACT

BENZOHETEROCYCLICALKYL DERIVATIVES OF 4-(2-KETO-1-BENZIMIDAZOLINYL)-PIPERIDINE, 4(2-KETO-1-BENZIMIDAZOLINYL)1,2,3,6-TETRAHYDROPYRIDINE, 1-PHENYL-1,3,8-TRIAZASPIRO(4,5)DECAN-4-ONE AND 2,4,9-TRIAZASPIRO(5,5)UNDECAN-1,3,5TRIONE IN WHICH THE BENZOHETEROCYCLIC MOIETY IS THIANAPHTHENYL OR BENZOFURANYL, OPTIONALLY SUBSTITUTED BY CHLORO, BROMO, FLUORO, METHYL, METHOXY OR TRIFLUOROMETHYL, HAVE NEUROLEPTIC ACTIVITY. THE COMPOUNDS ARE GENERALLY PREPARED FROM EITHER THE BENZOHETEROCYCLICALKYL HALIDE BY REACTION WITH THE APPROPRIATE AMINE OR THE BENZOHETEROCYCLIC AMINE BY CONDENSATION WITH A 5,5-BIS(B-HALOETHYL)BARBITURIC ACID.

3,629,267 BENZOHETEROCYCLICALKYL DERIVATIVES OF 4-(2-KETO1-BENZIMlDAZOLINYL)-PIPERIDINE, 4-(2-KETO 1 BENZIMIDAZOLINYL) 1,2,3,6TETRAHYDROPYRIDINE, 1 PHENYL 1,3,8- TRIAZASPIRO[4,5]DECAN 4 ONE AND2,4,9- TRIAZASPIRO[5,5]UNDECAN-1,3,5-TRIONE Carl Kaiser, Haddon Heights,N.J., and Charles L. Zirkle, Philadelphia, Pa., assignors to Smith Kline& French Laboratories, Philadelphia, Pa. No Drawing. Filed Oct. 28,1968, Ser. No. 771,320 Int. Cl. C07d 5/10, 6/18 US. Cl. 260-294.8 C 7Claims ABSTRACT OF THE DISCLOSURE Benzoheterocyclical'kyl derivatives of4-(2-keto-1-benzimidazolinyl) piperidine, 4-(2-keto-l-benzimidazolinyl)-1,2,3,6 tetrahydropyridine, 1 phenyl 1,3,8-triazaspiro- [4,51decan-4-oneand 2,4,9-triazaspiro[5,5]undecan-1,3,5- trione in which thebenzoheterocyclic moiety is thianaphthenyl or benzofuranyl, optionallysubstituted by chloro, bromo, fluoro, methyl, methoxy ortrifluoromethyl, have neuroleptic activity. The compounds are generallypre pared from either the benzoheterocyclicalkyl halide by reaction withthe appropriate amine or the ben-zoheterocyclic amine by condensationwith a 5,5-bis(B-haloethyl)- barbituric acid.

This invention relates to novel benzoheterocyclicalkyl derivatives of 4(2 keto-l-benzimidazolinyl)-piperidine, 4 (2 ketol-benzimidazolinyl)-1,2,3,6-tetrahydropyridine, 1 phenyl 1,3,8triazaspiro[4,5]decan 4-one and 2,4,9 triazaspiro[5,5]undecan1,3,5-trione. These compounds have useful pharmacodynamic activity andmore specificaly have neuroleptic activity as demonstrated in standardanimal pharmacological test procedures. Exemplary of the activity of thecompounds of this invention is the moderate to marked decreased motoractivity, catalepsy, hypotonia and ptosis produced in rats upon oraladministration of doses ranging from 1.0 to 50.0 mg./kg. At these dosesno toxicity is observed.

The compounds of this invention are represented by the following generalstructural formula:

FORMULA I in which:

R represents hydrogen, chloro, bromo, fluoro, methyl,

rnethoxy or trifluoromethyl; Y represents oxygen or sulfur;

n represents a positive whole integer from 2 to 4; and Z represents 7United States Patent ()ffice 3,629,267 Patented Dec. 21, 1971 Preferredcompounds include those of Formula I wherein R is in the 5 or6-position, Y is sulfur, n is 3 and the benzoheterocyclic moiety is3-substituted.

The compounds of this invention may be used in the form of apharmaceutically acceptable acid addition salt having the utility of thefree base. Such salts, prepared by methods well known to the art, areformed with both inorganic or organic acids, for example: maleic,fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicyclic,methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric,salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric and nitric acids.

The compouds of this invention wherein Z is 4-(2-ketov1-benzimidazolinyl)-1-piperidyl,4-(2keto-1-benzimidazolinyl)-l,2,3,6-tetrahydro-l-pyridyl or1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl-4-one are generally preparedfrom a benzoheterocyclical'kyl halide having the formula:

FORMULA II wherein R Y and n are as defined for Formula 'I and X ishalogen, preferably chlorine or bromine, by reaction with theappropriate amine (HZ). The halides of Formula II are prepared fromcorresponding alkanoic acids (n is l to 3) via reduction with lithiumaluminum hydride to the alcohol followed by reaction with a phosphorustrihalide, such as phosphorus tribromide, to give the alkyl halide. Therequired alkanoic acids are obtained as described in Belgian Pat. No.711,675.

The compounds of Formula I wherein Z is2,4,9-triazaspiro[5,5]undec-9-yl-1,3,5-dione are generally prepared froma benzoheterocyclicalkyl amine having the formula:

R1 $40112) 11-NH2 FO RMULA III wherein R Y and n are as defined inFormula I by reaction with a 5,5-bis(,3-haloethyl)-barbituric acidderivative, the halo group being iodo or bromo. The amines of FormulaI*I=I are prepared from corresponding alkanoic acids (11 is 1 to 3) viareacting the acid with thionyl chloride to give the acid chloride whichis treated with ammonia and reducing the resulting amide with lithiumaluminum hydride to yield the alkyl amine.

The compounds of this invention may be administered orally orparenterally in conventional dosage unit forms such as tablets,capsules, injectables or the like, by incorporating the appropriate doseof a compound of Formula I, either as the free base or an acid additionsalt thereof, with carriers according to accepted pharmaceuticalpractices.

The foregoing is a general description of how to prepare the compoundsof this invention. The following examples illustrate the preparation ofspecific compounds having neuroleptic activity. However this should notbe construed as limiting the scope of the invention since appropriatevariations in the starting materials will produce other products setforth hereinabove.

PREPARATIONS (A) 3-(3-thianaphthenyl)-propyl bromide (Formula II) To amixture of 4.0 g. (0.105 m.) of lithium aluminum hydride in 1000 ml. ofdry ether is added a solution of 10.7 g. (0.052 m.) of3-(3-thianaphthenyl)-propionic acid in 50 ml. of dry tetrahydrofuran,dropwise with stirring. The resulting mixture is stirred and refluxedfor four hours, decomposed and filtered. The dried filtrate isevaporated in vacuo and the residue distilled to give3-(3-thianaphthenyl)-propanol, B.P. 133-158 C./0.5 mm.

A solution of 9.2 g. (0.0479 m.) of 3-(3-thianaph thenyl)-propanol in250 ml. of dry ether is stirred while ml. of phosphorus tribromide in 50m1. of dry ether is added dropwise. The resulting mixture is stirred andrefluxed for one hour, poured into ice-water and the layers separated.The ether layer is washed, dried and evaporated in vacuo to give an oilwhich is distilled to give 3-(3- thianaphthenyl)-propyl bromide, B.P.147l90 C./ 0.1

(B) 3-(3-thianaphthenyl)-propyl amine (Formula III) A mixture of 5.2 g.(0.025 m.) of 3-(3-thianaphthenyl)-propionic acid and m1. (0.025 m.) ofthionyl chloride is allowed to stand at room temperature overnight,diluted with benzene and evaporated in vacuo to give the acid chloride.The latter is dissolved in ether and treated with an excess of aqueousammonia. The resulting mixture is refluxed for one hour and theseparated organic layer is washed, dried and concentrated to give 3-(3-thianaphthenyl)-propionamide. The amide is reduced with an equimolaramount of lithium aluminum hydride in dry ether to yield3-(3-thianaphthenyl)-propylamine.

Following the procedures of parts A or B above, other R -substitutedthianaphtheneor benzofuranalkanoic acids are similarly converted tocorresponding alkyl bromides or amines.

EXAMPLE 1 A mixture of 4.7 g. (0.0219 In.) of4-(2-keto-1-ben'zimidazolinyl)-1,2,3,G-tetrahydropyridine, 8.0 g.(0.0314 111.) of B-(B-thianaphthenyl)-propyl bromide, 1.84 g. (0.0219m.) of sodium bicarbonate and 0.3 g. of potassium iodide in 500 ml. ofdry toluene is stirred and refluxed for four days. The reaction mixtureis evaporated in vacuo and the residue is dissolved in chloroform/water.The water layer is washed with chloroform and the total chloroformsolution is washed with dilute hydrochloric acid, dried and evaporatedin vacuo to give 1-[3-(3- thianaphthenyl) propyl] -4-(2keto-l-benzimidazolinyl)- 1,2,3,G-tetrahydropyridine; hydrochloride M.P.252- 254 C.

Similarly, by employing 3-(5-chloro-2-thianaphthenyl)- propyl bromide(obtained from the propionic acid) in the above reaction there isproduced l-[3-(5chloro-2-thianaphthenyl) propyl] 4 (2 ketol-benzimidazolinyl)- 1,2,3,6-tetrahydropyridine.

EXAMPLE 2.

A mixture of 8.0 g. (0.0314 m.) of 3-(3-thianaphtheny1)-propyl bromide,4.4 g. (0.0203 In.) of 4-(2-ketol-benzimidazolinyl)-piperidine, 1.71 g.(0.0203 In.) of sodium bicarbonate and 0.3 g. of potassium iodide in 500ml. of dry toluene is stirred and refluxed for four days. The reactionmixture is evaporated in vacuo and the residue dissolved inchloroform/water. The layers are separated and further worked up as inExample 1 to yield 1-[3-(3 thianaphthenyl)-propyl] 4 (Z-keto-l- 4benzimidozolinyl)-plperidine; hydrochloride M.P. 287 294 C.

Similarly, by employing an equivalent amount of 3-(5- methyl 3thianaphthenyl)-propyl bromide (obtained from the propionic acid) asdescribed above there is prepared 1-[3-(5 methyl 3thianaphthenyl)-propyl]- 4-(2-keto 1 benzimidazolinyl)-piperidine.

EXAMPLE 3 Following the procedures of Example 1, a mixture of 5.0 g.(0.0216 In.) of l-phenyl 1,3,8 triazas'piro[4,5] decan-4-one, 8.0 g.(0.0314 111.) of 3-(3-thianaphthenyl)- propyl bromide, 1.82 g. (0.0216In.) of sodium bicarbonate and 0.3 g. of potassium iodide in 500 ml. ofdry toluene is stirred and refluxed for four days, then filtered whilehot. The filtrate is evaporated in vacuo and the residue worked up togive l-phenyl 8 [3-(3-thianaphthenyl)-propyl] 1,3,8triazaspiro[4,5]decan 4 one; hydrochloride M.P. 258-260" C.

Use of 3-(6-methoxy 2 thianaphthenyD-propyl bromide (obtained from thepropionic acid) as the reactant above yields l-phenyl 8[3-(6-methoxy-2-thianaphthenyl)-propyl] 1,3,8 triazaspiro[4,5]decan-4-one.

EXAMPLE 4 A solution of 6.0 g. (0.03 m.) of 3-(3-thianaphthenyl)-propylamine in 60 ml. of anhydrous ethanol is added to a suspension of11.7 g. (0.027 m.) of 5,5-bis(/3-iodoethyl) barbituric acid in ml. ofanhydrous ethanol and the mixture is shaken two and one-half hours inthe dark under nitrogen. One equivalent of dry silver oxide and, aftershaking for three days, one more equivalent of silver oxide is added.The mixture is then shaken for three hours, briefly heated to 60 C.,filtered and evaporated. The residue is purified by chromatography togive 9-[3- (3 thianaphthenyl)-propyl] 2,4,9 triazaspiro[5,5]undecan-l,3,5-trione.

Similarly, by reacting 3-(3 benzofuranyl)-propylamine (obtained from thepropionic acid) with 5,5-bis (13- iodoethyl)barbituric acid as describedabove there is prepared 9-[3-(3 benzofuranyl) propyl] 2,4,9triazaspiro[5,5]undecan-l,3,5-trione.

EXAMPLE 5 Following the procedure of Example 1, an equivalent amount of3-(2-benzofuranyl)-pr0pyl bromide (obtained from the propionic acid) isreacted with 4-(2-k'eto-1-benzimidazolinyl) 1,2,3,6 tetrahydropyridinein the presence of sodium bicarbonate and potassium iodide to yield uponworkup 1-[3-(2 benzofuranyl) propyl] 4 (2- keto 1benzimidazolinyl)-1,2,3,6-tetrahydropyridine.

By employing instead 3-(3-benzofuranyl)-propylbromide as the reactantabove there is obtained 1-[3-(3-benzofuranyl) propyl] 4 (2 keto 1benzimidazoliny1)- 1,2,3,6-tetrahydropyridine.

EXAMPLE 6 Following the procedure of Example 1, 3-(6-fiuoro-3-thianaphthenyl)-propyl bromide (obtained from the propionic acid) isreacted with 4-(2-keto-l-benzimidazolinyl)-1,2,3,6-tetrahydropyridine togive 1-[3-(6-fluoro-3-thianaphthenyl) propyl] 4 (2 keto 1benzimidazolinyl)-1,2,3,6-tetrahydropyridine.

Use of 3-(6-trifluoromethyl-3-thianaphthenyl)-propyl bromide asdescribed above yields 1-[3-(6-trifluoromethyl- 3 thianaphthenyl)propyl] 4 (2-keto 1 benzimidazolmyl)-1,2,3,6-tetrahydropyridine.

EXAMPLE 7 Following the procedure of Example 1, 3-(6-bromo-3-benzofuranyl)-propylbromide (obtained from the propionic acid) isreacted with 4-(2-keto-l-benzimidazolinyl)- 1,2,3,6-tetrahydropyridineto yield the product 1-[3-(6- bromo-3-benzofuranyl)-propyl] 4 (2 keto 1benzimidazolinyl)-1,2,3,6-tetrahydropyridine.

EXAMPLE 8 Following the procedures of Examples 1 and 3, a mixture of2-(3-thianaphthenyl)-ethyl bromide (obtained from the acetic acid) andl-phenyl-l,3,8-triazaspiro[4,5] decan-4-one is stirred and refluxed forfour days in the presence of sodium bicarbonate and potassium iodide toyield upon workup the product, 1-phenyl-8-[2-(3-thiannaphthenyl) -ethyl]-1,3,8-triazaspiro [4,5] decan-4-one.

Similarly, employing 4-(6-methoxy-3-benzofuranyl)- butyl bromide(obtained from the butyric acid) as described above results in theformation of 1-phenyl-8-[4- (6 -methoxy-3-benzofuranyl)-butyl] 1,3,8triazaspiro [4,5]decan-4-one.

What is claimed is:

1. A chemical compound of the formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein:

R is hydrogen, chloro, bromo, fluoro, methyl, methoxy ortrifiuoromethyl; Y is oxygen or sulfur; n is a whole integer from 2 to4; and Z is 2. A chemical compound according to claim 1 in which thebenzoheterocyclic moiety is 3-substituted and has the R substituent inthe 5 or 6-position.

3. A chemical compound according to claim 2 in which Y is sulfur and nis 3.

4. A chemical compound according to claim 3 in which R is hydrogen,chloro or fluoro.

5. A chemical compound according to claim 4 in which R is hydrogen,being the compound 1-[3-(3-thianaphthenyl)propyl]-4(2-keto-l-benzimidazolinyl) l,2,3,6- tetrahydropyridine.

6. A chemical compound according to claim 4 in which R is fluoro.

7. A chemical compound according to claim 4 in which R is chloro.

References Cited UNITED STATES PATENTS 3,196,157 7/1965 Janssen 260294.8

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner US. Cl.X.R.

260-240 J, 256.4 C, 256.5 R, 293.4 E, 294 A, 294.8 C, 295 AM, 330.5,340.3; 424200, 232, 251, 263, 267

